Nitro analogues of chlorambucil as potential hypoxia-selective anti-tumour drugs.
The chlorambucil isomer 4-[3-[N,N-bis(2-chloroethyl)amino]phenyl] butanoic acid (m-chlorambucil) has been synthesized for the first time, and the two isometric nitro derivatives of both m-chlorambucil and chlorambucil itself have been prepared as potential hypoxia-selective cytotoxins. Reduction potentials (E1/2) of the two nitro compounds were determined by cyclic voltammetry, and one-electron reduction potentials (E(1] were estimated. Both the chlorambucil isomers and the derived nitro compounds crosslink DNA, as determined by their cytotoxicity ratios in DNA repair-proficient and -deficient cell lines, but neither of the nitro derivatives showed selective toxicity under hypoxic conditions, probably due to their rather low reduction potentials.
Palmer
B D
BD
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Wilson
W R
WR
Denny
W A
WA
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects*; D002478:Cells, Cultured; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004563:Electrochemistry; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D010084:Oxidation-Reduction
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D002699:Chlorambucil